Streptococcus pneumoniae is the cause of a variety of common respiratory and systemic infections of infancy and early childhood such as pneumonia, otitis media, and meningitis. Such pneumoccocal infections can range in severity from asymptomatic to life threatening. The emergence of strains of S. pneumoniae that are resistant to a variety of antibiotics has resulted in a great need for improved methods of vaccination against S. pneumoniae. This need is especially acute in the case of children between the ages of 6 months and 24 months, in whom disease caused by S. pneumoniae can be especially severe.
S. pneumoniae is a gram-positive microorganism containing a cell wall surrounded by a polysaccharide capsule. The polysaccharide capsule is the primary virulence factor of S. pneumoniae and provides the basis for type-specific identification of approximately 90 different serotypes. Capsular polysaccharides stimulate the production of type-specific antibodies that can confer protection against S. pneumoniae (Fedson, 1988, in Vaccines (Plotkin and Mortimer, eds.), E.B. Saunders Co., Philadelphia, pp. 271-299 [Fedson]; Prober et al., 1983, J. Infect. Dis. 148:427-435; Koskela et al., 1982, Pediatr. Infect. Dis. 1:245-252). It is generally accepted in the art that the higher the level of a particular type-specific antibody, the greater the level of protection against that particular serotype of S. pneumnoniae. Thus, in the absence of human efficacy trials, the measurement of antibody levels following vaccination has come to be the art-recognized method of evaluating the effectiveness of new vaccines or new methods of vaccination. See, e.g., Fedson, at page 279: "Clinical and experimental observations have firmly established the association between the presence of type-specific serum antibody and the protection against infection by homologous pneumococcal organisms." See, also, Schiffiman et al., 1980, J. Immunol. Meth. 33:133-144 ("Antibodies to pneumococcal capsular polysaccharides are determined for the following reasons: (1) to ascertain the immune response to a vaccine in order to assess protection against pneumococcal types in the vaccine . . . "). Accordingly, there has been much effort expended in attempts to develop vaccines that will raise the level of type-specific antibodies to S. pneumoniae in vaccinees.
Currently licensed vaccines against S. pneumoniae are based on a combination of pneumococcal polysaccharides that are present in unconjugated form. For example, PNEUMOVAX.RTM.23, produced by Merck Sharp & Dohme, West Point, Pa., consists of a combination of 23 different purified pneumococcal polysaccharides. PNU-IMUNE.RTM.23 is an unconjugated vaccine produced by Lederle Laboratories, Pearl River, N.Y., containing the same 23 capsular polysaccharide antigens as is contained in PNEUMOVAX.RTM.23.
While such unconjugated pneumococcal polysaccharide vaccines are highly effective in many patient populations, they are often not very effective in children younger than two years of age (Douglas et al., 1983, J. Infect. Dis. 148:131-137; Ahonkai et al., 1979, New Eng. J. Med. 301:26-27; Sell et al., 1981, Rev. Infect. Dis. 3:S97-S107). This is probably due to the immaturity of T cell independent humoral immune responses at that age. The lack of efficacy of unconjugated pneumococcal polysaccharide vaccines in children younger than two years old has led some researchers to conclude with respect to unconjugated vaccines that "The immunogenicity of polysaccharide pneumococcal vaccine . . . is absent or minimal for most of the capsular polysaccharides in children younger than 2 years of age. Hence, vaccination is not indicated until 2 years of age." (Peter & Klein, 1996, Pediatrics in Review 17:335-341).
As a result of the lack of immunogenicity of unconjugated pneumococcal polysaccharide vaccines in children less than two years old, alternative vaccines have been sought. Some pneumococcal vaccines that are currently under development or in clinical testing utilize pneumococcal polysaccharides that have been conjugated to protein carriers. For example, PCV is a heptavalent conjugated pneumococcal polysaccharide vaccine produced by Merck Sharp & Dohme, West Point, Pa. PCV consists of seven serotypes of pneumococcal polysaccharides (4, 6B, 9V, 14, 18C, 19F, and 23F according to the Danish nomenclature) that have been conjugated to the outer membrane protein complex of Neisseria meningitidis. One hope for such conjugated pneumococcal polysaccharide vaccines is that they will be able to induce a better immune response in young children because, since these conjugated vaccines contain carrier proteins, they will be able to stimulate T cell dependent pathways of humoral immunity while unconjugated polysaccharide vaccines may be restricted to stimulating antibody production by T cell independent pathways. T cell dependent pathways of humoral immunity are not age-dependent and exist at birth.
Evidence that conjugated pneumococcal polysaccharide vaccines may be useful in very young children has been presented. Some investigators have used four doses of conjugated vaccine at 2, 4, 6, and 12 months. Other approaches utilized unconjugated instead of conjugated vaccine at age 12 months. For example, Anderson et al., 1996, J. Pediatrics 128:649-653 (Anderson) vaccinated children at 2, 4, and 6 months of age with a conjugated pneumococcal polysaccharide vaccine (PCV) and followed with a single dose of unconjugated polysaccharide vaccine (PNEUMOVAX.RTM.23) at age 12 or 15 months. This vaccination schedule resulted in a significant increase in antibody titers to all seven serotypes in the conjugated vaccine. However, an effective vaccination regimen that makes use of unconjugated vaccine at the age of six months or younger has not been reported. Accordingly, despite such studies as that of Anderson, there remains a great need for developing even more highly effective methods of immunizing young children against S. pneumoniae utilizing conjugated and unconjugated pneumococcal polysaccharide vaccines.